**1. Introduction**

DNA sequencing technology and bioinformatics have made it possible to evaluate the composition of the diverse community of bacteria, archaea, fungi, viruses, and other organisms that form the microbiome. A growing body of research has now correlated the microbiome with a wide variety of diseases [1–4]. The microbiome is present in many parts of the body but the largest collection of over 30 trillion bacteria is in the gu<sup>t</sup> [5].

The gu<sup>t</sup> microbiome participates in vital processes including digestion, energy homeostasis and metabolism, the synthesis of vitamins and other nutrients, and the development and regulation of immune function. It also contributes to the production of numerous compounds that enter the blood and a ffect various tissues and organs of the body [3,4].

An important consideration is the recognition of the enormous variation in the gu<sup>t</sup> microbiota composition in each individual, as well as in each area of the digestive tract. Throughout the intestines there are specific niches that house individual microbial communities, which can be immunologically more active than others. A balanced and diverse microbiome is critical for maintaining health and immunological balance [6,7].

When the microbiome is in balance it contributes to many health benefits, but when out of balance, it can cause problems in the gu<sup>t</sup> and other areas of the body. Dysbiosis arises when the delicate and elaborate ecology of microbial communities are disrupted by internal or external factors. A disrupted microbiome is characterized by the overgrowth of one or more of the di fferent microbial colonies. A complex interaction between the microbiome and immune systems may result in an inflammatory state [8,9]. An imbalanced microbiome has been associated with a number of gastrointestinal diseases including irritable bowel syndrome (IBS) and inflammatory bowel disorder (IBD) [10–12]. Conditions such as asthma, atopy, childhood obesity, and autism spectrum have been correlated with excess antibiotic use and a resulting alteration in the microbiome in childhood [13–16]. Numerous other conditions such as obesity, autoimmune disorders, cardiovascular disease, cancer, and neurological disorders have also been linked with changes in the microbiome [1–4,17–19].

Diet can rapidly alter the composition of the microbiome [20–23]. A western diet high in meat products, providing nutrients such as choline and carnitine, can cause certain gu<sup>t</sup> bacteria to produce trimethylamine (TMA). TMA is absorbed into the bloodstream and then oxidized in the liver to form trimethylamine-N-oxide (TMAO). High levels of TMAO have been suggested to contribute to cardiovascular disease by interfering with cholesterol metabolism and transportation, foam cell formation, and platelet aggregation [24–34].

Gut bacteria may also a ffect cardiovascular disease by a decrease in fiber intake. Dietary fiber is a rich source of food for gu<sup>t</sup> bacteria and its reduction can lead to a decreased bacterial production of the short chain fatty acid butyrate. This change can lead to dysbiosis and local inflammation in the gu<sup>t</sup> lining, resulting in impaired gu<sup>t</sup> barrier function and the possible leakage of bacterial toxins, such as lipopolysaccharides, into the bloodstream [30–34].

There are other microorganism communities throughout the body which can contribute to health and disease. At one time, the lung was considered a sterile organ, but we now recognized that it has its own microbiome which extends into the lower lung. There is cross talk between the lung and gu<sup>t</sup> microbiomes, which could be relevant to patients with COVID 19 that display gastrointestinal symptoms [35–38].

The gu<sup>t</sup> microbiome also a ffects the brain and mental health. The basis for this interaction is the gut–brain axis, which consists of the brain, immune system, endocrine system, enteric nervous system (ENS), enteroendocrine system (EEC), and the gu<sup>t</sup> bacteria. There is a bidirectional flow of information between the gu<sup>t</sup> and brain. The most direct is through the vagus nerve, which is an important and long nerve in the body that regulates many internal functions. A less direct means of communication is through di fferent chemical messengers, such as neurotransmitters, hormones, and peptides. The gu<sup>t</sup> produces numerous peptides and neurotransmitters. Many of these are also found in the brain. The secretion of these gut-derived chemicals can be influenced by the composition of the gu<sup>t</sup> microbiome. In addition, the gu<sup>t</sup> microbiome can also produce its own unique array of chemical messengers, that go into the bloodstream and a ffect di fferent parts of the body. There is also research showing that gu<sup>t</sup> microbes can activate immune cells in the gu<sup>t</sup> wall, which causes the release of proinflammatory cytokines and ultimately may a ffect the permeability of the blood–brain barrier [39–41]. Animal studies have shown that a disrupted microbiome can cause anxiety-like and depression-like behaviors [42,43]. A new field of psychobiotics has even emerged, which utilizes probiotics to a ffect moods and behavior in humans [44].

While the precise manner in which the microbiome participates in these many disease states is still not completely clear, there are currently a number of therapeutic approaches that are now being tested in clinical trials including diet, prebiotics, probiotics, antibiotics, and fecal microbiome transplantation (FMT) [45–47]. Recent studies, for example, have utilized personalized nutritional advice based on microbiome data and other factors [48–50]
